Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer

By Qing Chen, A. Boire, Xin Jin, M. Valiente, E. E. Er, A. López-Soto, Leni S. Jacob, R. Patwa, Hardik Shah, Ke Xu and 2 more. Nature, 2016

888 citations recorded by the source corpus.

Brain metastasis represents a substantial source of morbidity and mortality in various cancers, and is characterized by high resistance to chemotherapy. Here we define the role of the most abundant cell type in the brain, the astrocyte, in promoting brain metastasis. We show that human and mouse breast and lung cancer cells express protocadherin 7 (PCDH7), which promotes the assembly of carcinoma–astrocyte gap junctions composed of connexin 43 (Cx43). Once engaged with the astrocyte gap-junctional network, brain metastatic cancer cells use these channels to transfer the second messenger cGAMP to astrocytes, activating the STING pathway and production of inflammatory cytokines such as interferon-α (IFNα) and tumour necrosis factor (TNF). As paracrine signals, these factors activate the STAT1 and NF-κB pathways in brain metastatic cells, thereby supporting tumour growth and chemoresistance. The orally bioavailable modulators of gap junctions meclofenamate and tonabersat break this paracrine loop, and we provide proof-of-principle that these drugs could be used to treat established brain metastasis.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/5216bdeda360c47b54550af524e692d822b4fa45

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Citations in the corpus

cGAS in action: Expanding roles in immunity and inflammation (2019, background): “This intercellular cGAMP-mediated effector response has been proposed to support growth of brain metastatic cells by promoting a tumor-conducive cytokine environment (43).”
Mitochondrial DNA in inflammation and immunity (2020, positive): “For example, in the context of cell death, does production of cGAMP in apoptotic cells transfer to healthy apoptotic cells via gap junctions to promote a death-resistant state, in a manner similar to what has been observed in astrocytes [71]?”
Electrical and synaptic integration of glioma into neural circuits (2019, positive): “We then targeted gap junction-mediated amplification of neuronal activity-dependent potassium currents using the brain-penetrant gap-junction blocker meclofenamate 25 .”
EMERGING BIOLOGICAL PRINCIPLES OF METASTASIS (2017, positive): “In one recent example, breast carcinoma cells that colonize the brain have been found to benefit from communication with astrocytes through the assembly of gap junctions established between cancer cells and astrocytes (Chen et al., 2016).”